Atorvastatin is an effective inhibitor of HMG-CoA reductase, and is thus effective in treating hyperlipemia. It has been commercially available in the name of Lipitor™.
There have been numerous researches conducted regarding the synthesis of atorvastatin [WO 98/04543, U.S. Pat. Nos. 5,124,482, 5,216,174 and 5,273,995, U.S. Patent Publication No. 2004/0072893, Korean Patent No. 75791, J. Med. Chem., 1991, 34, 357-366].
The most common process for preparing atorvastatin known so far is shown in Scheme 1 below. According to the preparation process of Scheme 1, the compound of Chemical Formula 10-A with chiral cis-diol structure is obtained by way of the reaction intermediate of the Chemical Formula 16.

Specifically, the starting material ethyl α-bromo-4-fluorobenzene acetate of Chemical Formula 12 is reacted with ethyldioxalane ethylamide to obtain the compound of Chemical Formula 13. Subsequently, the tertiary amine compound of Chemical Formula 14 is prepared and cyclized to obtain the compound of Chemical Formula 15 with atorvastatin frame structure. After preparing the compound of Chemical Formula 16 by converting the oxalane group to aldehyde, the compound of Chemical Formula 17 is obtained through a multi-step process consisting of at least three steps. Subsequently, the ketone group of the compound of Chemical Formula 17 is reduced to obtain the compound of Chemical Formula 10-A with chiral cis-diol structure, and atorvastatin is obtained following several steps.
However, the conventional preparation process according to Scheme 1 is limited to be applied industrially for the following reasons:
1) According to Scheme 1, the cis-diol chiral structure is induced at a later stage through reduction of the ketone group following N-alkylation and cyclization. That is, several steps are added in order to delay the inducement of the cis-diol chiral structure of the compound of Chemical Formula 10-A. This is economically unfavorable. In addition, it is needed to maintain ultra-low reaction temperature (−78° C.).
2) The cyclization of the compound of Chemical Formula 14 with N,3-diphenylpropynamide is performed in the presence of acetic anhydride at 100° C. or higher. Following the reaction, the acetic anhydride should be removed by concentration, a not-an-easy task. As a result, the yield of the cyclization reaction is very low (43%).
3) The conversion of the oxalane group of the compound of Chemical Formula 15 to aldehyde group has to be performed for a long time of 48 hours under reflux condition, which is limited in industrial application. Also, the yield is not good (68.5%).
For the aforesaid reasons, the process for preparing atorvastatin according to Scheme 1 is not industrially applicable. Therefore, an improved version of the process for preparing atorvastatin was disclosed based on the conventional method according to Scheme 1 and is summarized in Scheme 2 below:

In the preparation process according to Scheme 2, the compound of Chemical Formula 10-A with a frame structure of atorvastatin is prepared following the cyclization of the compound of Chemical Formula 4-A and the compound of Chemical Formula 11.
The compound of Chemical Formula 4-A and the compound of Chemical Formula subjected to the cyclization are prepared by Schemes 2a and 2b, respectively:

However, the improved preparation process according to Scheme 2 is also limited in its industrial applications for the following reasons:
1) The cyclization to prepare the compound of Chemical Formula 9-A has to be performed at 100° C. or higher for over 48 hours.
2) The compounds used in the cyclization are prepared through multi-step processes. Especially, with the preparation yield of the 4-(4-fluorophenyl)-2-isobutyryl-3-phenyl-4-oxo-N-phenyl-butyrylamide compound of Chemical Formula 11 being 35% or below, the synthesis process of the reactants is uneconomical.
3) Because the chiral dihydroxy group of the compound of Chemical Formula 9-A is protected by 2,2-dimethyldioxane, deprotection is not easy.
4) In order to deprotect the compound of Chemical Formula 9-A, the compound has to be exposed to 80° C. or higher over 8 hours in the presence of excess (20% w/v or more, based on the compound) acid. Further, the yield is only 65% or below.
For the aforesaid reasons, the improved process for preparing atorvastatin according to Scheme 2 is also industrially inapplicable, because it requires a harsh reaction condition and gives low production yield and purity.
As an alternative, Korean Patent Publication No. 2004-84915 has disclosed a compound of Chemical Formula 4-B as intermediate for synthesis of atorvastatin, which has a chemical structure relatively easy to protect and deprotect:

When compared with the compound of Chemical Formula 4-A, in which the dihydroxy group is protected by 2,2-dimethyldioxane, the compound of Chemical Formula 4-B requires a milder condition for protection and deprotection and provides improved yield.
As described above, the conventional preparation processes of atorvastatin of Chemical Formula 1 are limited in industrial application.